In this application, a group of Harvard University investigators seeks funding to purchase an ultra high resolution computed tomography system for 3-dimensional structural analyses of developing, growing and aging bones, joints, teeth, eyes and blood vessels of genetically modified mice. The goal is to stimulate funded research projects on disease mechanisms of inherited disorders of the skeleton, osteoporosis, osteoarthritis, inflammatory bone loss, degenerative eye diseases and vascular anomalies and accelerate progress in studies of bone repair and tooth regeneration. Existing and new mouse models of disease will be used to identify critical mechanistic steps in disease progression, identify novel targets for therapy and strategies for repair/regeneration. Many of the genetic alterations in the mice being studied are identical to gene mutations responsible for inherited disorders in humans, while others are affecting processes that are altered in human disease. The data resulting from this research are therefore highly relevant to understanding mechanisms of human disease. The proposed high resolution Xradia MicroXCT-200 scanner, currently unavailable at Harvard Medical School/Harvard School of Dental Medicine, will enable investigators to address critical questions and collect data that are beyond the limits of current imaging technology. The instrument incorporates several innovative technical features that enable it to outperform all other 3-dimensional X-ray microscopes currently on the market for micro-tomography of biological samples. With proprietary PhaseEnhanced detectors, the MicroXCT makes high resolution (submicron) 3-dimensional histology of both mineralized and soft tissues possible. By combining innovative use of contrast-enhancing techniques of electron microscopy with ultrahigh resolution microCT the investigators believe data can be acquired even in cases where X-ray imaging is otherwise impossible. The acquisition of the instrument will accelerate outstanding research into disease- associated processes in mouse models of human diseases. PUBLIC HEALTH RELEVANCE: This project proposes the use of a new high resolution computed tomography instrument, Xradia MicroXCT-200, to obtain three-dimensional images of normal and diseased bones, cartilage, eye tissues and blood vessels in mouse models of human diseases. The instrument has capabilities that go beyond those of existing microCT scanners and will enable investigators to collect novel data on the progression and consequences of disease-causing processes in both mineralized and soft tissues. This new technology will accelerate progress in a number of existing research projects and generate new insights related to major diseases, such as genetic disorders of bones and joints, osteoporosis, arthritis, vascular anomalies, macular degeneration, periodontal disease and tumors.